Avaliação da resposta inflamatória na progressão tumoral do carcinoma mamário murino 4T1 após o tratamento com diferentes doses de talidomida

Abstract

In addition to the high antiangiogenic potential through inhibition of growth factors, the properties of thalidomide described in the literature also demonstrate control of some neoplasms by modulating the immune system. Although the mechanisms of action of thalidomide are poorly understood, clinical essays search to demonstrate the effect of this drug in neoplasm control. The aim of this work was to evaluate the effect of the treatment with different doses of thalidomide in the inflammatory response associated to tumoral progression of the 4T1 murine mammary carcinoma. A 4T1 cell suspension was inoculated in Balb/c mice in order to obtain a solid tumor. After the fifth day of inoculation, different groups of animals received 50 mg/kg, 100 mg/kg, and 150mg/kg per day of thalidomide through oral administration. Treatment continued for 23 days and on the 29th day following tumor inoculation the animals were euthanized. Primary tumor and lungs were collected for the evaluation of the inflammatory infiltrate through optical microscopy in HE and TNF-, CCL2/MCP-1, and VEGF cytokines and NAG and MPO enzymes were evaluated. An increase in mononuclear pattern of inflammatory cells was observed in the primary tumor. These cells were diffusely distributed in the peritumoral region of animals treated with 100mg/kg and 150 mg/kg of thalidomide. In the pulmonary metastases the inflammatory infiltrate varied among groups, with polymorphonuclear cells predominating. The levels of NAG and MPO in pulmonary metastases demonstrated a significant increase in animals treated with higher doses, result not demonstrated in the primary tumor. A significant reduction was observed solely in MCP-1 and VEGF levels in the primary tumor following treatment with thalidomide. However, a significant increase in MCP-1 and TNF- levels was observed in the lung. These results suggest that thalidomide therapy administered in higher doses possesses an antiangiogenic effect, possibly due to a decrease in macrophages reducing growth factor secretion. Thalidomide promoted a proinflammatory profile in pulmonary metastases, which may be associated to an immune system response against metastases.